The long-term goals of the studies proposed in Project 1 are to identify the molecular mechanisms responsible for the occurrence and characteristic features of juvenile (infantile) hemangiomas in humans. We have demonstrated that vascular endothelial cells isolated from hemangioma lesions are clonal populations and show increased migration and proliferation in culture. They also show an abnormal migratory response to endostatin, an antiangiogenic proteolytic fragment derived from the non-fibrillar collagen XVIII. To test the hypothesis that hemangiomas are caused by somatic mutations in genes involved in the regulation of endothelial cell behavior, several alternative strategies are proposed to identify the responsible genes. Collaborative mapping studies to identify hemangioma gene loci for families with inherited hemangioma are also planned. Identified hemangioma genes will be functionally tested for their ability to induce a cellular phenotype that is characteristic of hemangioma endothelial cells when transfected into normal endothelial cells. The studies are expected to provide novel insights into mechanisms responsible for the formation of hemangiomas and increase the understanding of how endothelial cell behavior is regulated. This understanding forms the required basis for development of antiangiogenic therapies for cancer, rheumatoid arthritis and other major pathological conditions.